This is a relatively common problem in certain breeds of horse and pony. Hyperlipidaemia is defined as the presence of excess fat or lipid in the blood. The term Hyperlipaemia is used when lipids in the blood reach a level to cause sample discolouration.
There is a strong breed predisposition for hyperlipaemia. Breeds at greatest risk for hyperlipaemia include Miniature horses, ponies, mules and donkeys. It can also be a condition of Quarter Horses, Paso Finos, Peruvian Pasos, and Tennessee Walking Horses. These are also breeds at risk for Equine Metabolic Syndrome. The disease can be seen in adults of any age.
Hyperlipaemia can occur in these breeds under a variety of circumstances. Any condition that causes a reduction in feed intake can predispose to fat mobilization. Other factors that predispose to hyperlipaemia include pregnancy, lactation, stress, and obesity.
What is happening?
The imbalance between caloric intake and energy demands leads to exhaustion of glycogen energy stores, particularly in the liver. This causes widespread mobilization of adipose (fat) tissue. Obese animals have very large fat stores.
Lipolysis, the mobilization of fat, leads to the release of free fatty acids (FFAs), non-esterified fatty acids (NEFAs), and glycerol into the circulation. White adipose tissue is actually a dynamic tissue that is made up of immune cells, stem cells, blood vessels, sympathetic innervation, pre-adipocytes, and adipocytes. Adipose tissue also produces adipokines (adiponectin, leptin, visfatin) and can release inflammatory mediators and pro-inflammatory cytokines. Adipocytes contain triacylglycerols (TAGs) as a single large droplet that takes up most of the cell. Triacylglycerol contains glycerol and fatty acids. These cells are constantly storing and releasing lipids. In times of positive energy balance, where caloric intake is increased and/or physical activity is limited, then fat storage increases leading to obesity. Conversely, during periods of caloric deprivation and/or increased physical activity lipolysis takes over. The balance between lipogenesis (fat storage) and lipolysis (fat mobilization) is also impacted by hyperlipidaemia/hyperlipaemia, obesity, and insulin resistance. Lipolysis is controlled by three enzymes, adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MGL).
After mobilization from adipose tissue glycerol and NEFAs arrive at the liver to be transformed into glucose, through the TCA cycle (oxidation of NEFAs) and gluconeogenesis (glycerol). Some of these products are then resynthesized to triglycerides, which are stored in the liver or transported as very low density lipoproteins (VLDLs). Under normal circumstances the VLDLs are removed from the blood and are incorporated back into adipose tissue. This important step is limited by the availability and activity of the enzyme, lipoprotein lipase. This enzyme is located in endothelial cells.
This balance between lipid deposition, lipid conversion to glucose in the liver, and lipid mobilization is easily disturbed and the system frequently overwhelmed with the end-result being high levels of triglycerides (VLDLs) circulating in the blood and fat deposition into the liver (fatty liver; hepatic lipidosis) and other tissues.
Role of insulin
This pathway is heavily influenced by insulin. Insulin prevents hyperlipaemia by inhibiting lipolysis and stimulating lipogenesis. This is primarily through inhibition the enzymes that mobilize fat, adipose triglyceride lipase and hormone-sensitive lipase, and by stimulating the enzyme that favours fat deposition, lipoprotein lipase. Insulin also stimulates gluconeogenesis in the liver. The effects of insulin are antagonized by glucocorticoids, catecholamines, ACTH and progesterone. The interaction between ACTH and insulin is particularly interesting, given that many aged ponies have concurrent Pars Pituitary Intermedia Dysfunction (PPID) with high levels of ACTH, and Equine Metabolic Syndrome with high levels of insulin.
The interactions between Equine Metabolic Syndrome, diabetes mellitus and hyperlipidaemia/hyperlipaemia is important, particularly as it relates to the impacts of lowering insulin levels with sodium-glucose cotransporter-2 (SGLT-2) inhibitors.
Signs of hyperlipaemia
Typically the early signs are vague, however most, but not all, will be quiet, depressed and inappetant. Other signs may include icterus, weakness, persistent recumbency, diarrhoea and colic. The initial signs of hyperlipaemia could easily be confused with the primary or initiating disease process, leading to a delay in diagnosis. As the disease progresses the animal appears obtunded.
Diagnosis
It is critical when dealing with susceptible breeds to always consider the possibility of hyperlipidaemia and hyperlipaemia. Diagnoses and early intervention are keys to a positive outcome.
Blood sampling will establish the diagnosis and gauge the severity of changes. The blood sample will be grossly discoloured when the triglycerides exceed 500 mg/dL (5.64 mmol/L). This value is used to provide a numeric differential between hyperlipidaemia and hyperlipaemia. Normal triglyceride concentration in horse and ponies should be less than 85 mg/dL (<1 mmol/L). However, triglyceride levels in normal ponies and donkeys can reach 290 mg/dL (2.94 mmol/L) without concern. Horses and ponies with EMS may normally have elevated levels of triglycerides without adverse effects.
Although not routinely measured NEFAs, VLDLs and cholesterol are all elevated.
Fat deposition within the liver leads to hepatic dysfunction. This can be assessed by the magnitude of increases in GLDH, SDH, GGT, ALP, AST, ammonia, bilirubin and bile acids. The diagnosis of hepatic lipidosis is suspected on ultrasound and confirmed through biopsy. Ultrasound reveals an enlarged and diffusely hyperechoic liver. The intrahepatic portal vessel walls are hard to identify.
Metabolic acidosis is common. Azotemia is also frequently reported, although lipaemia can cause false elevations in creatinine.
Treatment and Prognosis
The basis of treatment is to create a positive energy balance to reduce fat mobilization and encourage fat deposition in peripheral tissues.
Highly palatable and good quality feeds should be offered. This includes cereal grains, molasses and good quality hay. If there is total refusal of feed, which is common, intravenous fluids containing 5% dextrose should be administered at maintenance rates (50 mL/kg bodyweight/day). Supplementation with potassium is important.
Animals under treatment should be monitored closely for increases in blood glucose. This is because many have peripheral resistance. This may prompt insulin therapy.
A common field treatment for 200 kg pony, day 1: 30 IU protamine zinc insulin and 100 gm glucose PO twice daily; days 2-5: 15 IU insulin IM BID with 100 gm of glucose.
Heparin administration was advocated as it is thought to stimulate lipoprotein lipase, the enzyme that promotes lipogenesis (fat storage). However, heparin has fallen out of favour as it has been demonstrated that lipoprotein lipase is maximally stimulated during hyperlipaemia.
The prognosis for life is poor for ponies with hyperlipaemia and hepatic lipidosis. Miniature Horses have a better outlook, especially if the triglyceride levels remain beneath 1200 mg/dL (13.5 mmol/L). Horses who have triglyceride levels that exceed 2000 mg/dL (22.6 mmol/L) almost always fail to survive, although there are some important exceptions.
Exceptions to the rule
There are rare horses that will have significantly elevated triglycerides in the absence of significant clinical signs. These horses appear to have insulin-dependent diabetes mellitus. Triglyceride values exceeding 3000 mg/dL (34 mmol/L) have been reported in these horses and ponies. The triglyceride levels decrease with exogenous insulin. This highlights the role of insulin in the inhibition of lipolysis.
The other group that requires reference are those ponies with Equine Metabolic Syndrome (EMS) that are on SGLT-2 inhibitors. There are transient increases in triglycerides beginning in the week after starting these medications. It is possible that these (usually) ponies have been under the inhibitory effects of high levels insulin on fat mobilization and the reduction in insulin caused by these drugs causes a ‘release’ on this inhibition, with an increase in lipolysis. Our knowledge around this response requires research, although it would be prudent to stop medication if the animal becomes inappetant for some reason. It is also important that blood work is performed prior to starting treatment.
These examples highlight the importance of insulin on fat cycling in ponies and horses.
It has been suggested that carnitine supplementation may be helpful in the utilization of fatty acids by tissues, including skeletal and cardiac muscle. Carnitine is required to transport acyl-CoA (from long chain fatty acids) from the cell cytoplasm into the mitochondrial matrix as acylcarnitine. Acylcarnitine is then broken down to acyl-CoA and free carnitine. The acyl-CoA is used a fuel source via Beta oxidation and the free carnitine is transported out of the mitochondria to the cell cytoplasm. Oral carnitine supplements appear to be poorly absorbed in horses, but a dose of 10 grams per day of L-carnitine has been shown to increase carnitine levels in the blood.
The take home message is that if you own a horse of one of the susceptible breeds then avoid obesity at all costs. Furthermore, if the horse or pony goes through a period of inappetence contact your veterinarian sooner rather later.
Tags: Endocrine and Metabolic